EP1309538B1 - Procede de production d'acides benzoiques substitues par trifluoroethoxy - Google Patents

Procede de production d'acides benzoiques substitues par trifluoroethoxy Download PDF

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Publication number
EP1309538B1
EP1309538B1 EP01960238A EP01960238A EP1309538B1 EP 1309538 B1 EP1309538 B1 EP 1309538B1 EP 01960238 A EP01960238 A EP 01960238A EP 01960238 A EP01960238 A EP 01960238A EP 1309538 B1 EP1309538 B1 EP 1309538B1
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Prior art keywords
hal
denotes
formula
trifluoroethoxy
reaction
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EP01960238A
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German (de)
English (en)
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EP1309538A2 (fr
Inventor
Kai Fabian
Steffen Enke
Herbert Tilly
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Merck Patent GmbH
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Merck Patent GmbH
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/122—Halides of copper
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • Trifluoroethoxy-substituted benzoic acid derivatives of the formula I are useful synthetic building blocks, for example for the preparation of medicaments.
  • the compound 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid is an important intermediate in the synthesis of the active ingredient flecainide acetate, an antiarrhythmic agent known from US 3,900,481.
  • GB 2045760 describes a process for preparing 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid by first adding hydroquinone or 1,4-dibromobenzene with 2,2,2-trifluoroethyl trifluoromethanesulfonate or trifluoroethanolate to give 1,4-bis (2,2,2-trifluoroethoxy) benzoic acid.
  • Di- (trifluoroethoxy) benzot is reacted, the acetyl group is introduced in the o-position to a trifluoroethoxy substituent by acetylation in the presence of a Lewis acid and subsequently oxidized to the desired benzoic acid.
  • WO 98/47853 are halogenated benzoic acids or their salts with 2,2,2-trifluoroethanol in the presence of a strong base and a
  • Reacted copper-containing material and optionally worked up acid corresponds to an Ullmann reaction.
  • an aprotic solvent in particular the solvent N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, pyridine, collidine, dimethyl sulfoxide, hexamethylphosphoramide or mixtures thereof, is considered to be advantageous.
  • trifluoroethanol can also be used as a solvent itself.
  • Strong bases suitable for the method described are sodium, NaH, NaNH 2 , sodium or potassium alkoxides, NaOH, KOH, nitrogen-substituted amidines, guanidines or tetraalkylammonium hydroxides.
  • sodium hydride is disclosed.
  • the reaction temperature is preferably 110-115 ° C, due to DMF as the preferred solvent.
  • the reaction product precipitates together with the resulting copper salts and by-products and is filtered off.
  • the residue is first taken up in 5% KOH and the solution filtered through Celite.
  • the remaining alkaline solution is extracted several times with, for example, dichloromethane and then the product is precipitated from the alkaline solution with hydrochloric acid and recrystallized.
  • the invention therefore an object of the invention to develop an improved process for the preparation of trifluoroethoxy-substituted benzoic acid derivatives of the formula I.
  • the improved process should be particularly suitable for large-scale synthesis.
  • the method according to the invention represents a selection invention to the method described in WO 98/47853.
  • the use of the solvent tetrahydrofuran in the presence of dilute hydrochloric acid facilitates the separation of the copper salts formed from the reaction.
  • the work-up by the process of the invention requires compared to WO 98/47853 a smaller number of operations, since the product remains dissolved in THF, while the copper salts and by-products remain in the aqueous phase in a predominant amount.
  • the post-extraction with a halogenated solvent as described for the process of WO 98/47853.
  • the process according to the invention is particularly suitable for large scale synthesis, i. preferably for the production of products in the range of 1 kg to 500 kg.
  • A is alkyl and has 1 to 4, preferably 1, 2 or 3, C atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Most preferably, A is methyl.
  • Ar is preferably unsubstituted phenyl or naphthyl, more preferably by A, OH, OA, CF 3 , OCF 3 , CN or NO 2 mono-, di- or trisubstituted phenyl.
  • A has one of the preferred meanings given above. More preferably, Ar is unsubstituted phenyl.
  • O (CO) Ar is preferably benzoyl.
  • Hal is preferably F or Cl.
  • X is preferably Cl or Br.
  • R or R 1 are each independently A, OA, COOH, COOA, SA, CF 3 , OCF 3 , CN, NO 2 , Hal, - (CH 2 ) p -Hal, -O- (CH 2 ) p -Hal , -S- (CH 2 ) p -Hal, Ar, - (CH 2 ) p -Ar, OAr, O (CO) Ar, NH 2 , NHA, NA 2 , CONH 2 , CONHA or CONA 2 .
  • Particularly preferred for R and R 1 each independently is A, OA or NH 2 .
  • R and R 1 are H.
  • n is preferably 1 or 2, more preferably 2.
  • m is preferably 0 or 1, more preferably 0.
  • o is preferably 0.
  • the inventive method is particularly suitable for the synthesis of 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid.
  • halogenated benzoic acid derivatives of the formula II are commercially available or can be prepared by methods known per se, e.g. in Houben-Weyl, Methods of Organ. Chemistry described.
  • Preferred starting material for the synthesis of 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid is 5-bromo-2-chlorobenzoic acid.
  • a salt of the benzoic acid derivatives of the formula II for example a sodium or potassium benzoate of the formula II, is also suitable as starting material in the process according to the invention.
  • Phase transfer catalysts from the class of tris (polyoxaalkyl) amines are known from Ullmann and Ullmann analogous reactions from the literature (Ref .: G. Soula, J. Org. Chem. 1985, 50, 3717-3721 or Rewcastle et al , J. Med. Chem. 1989, 32, 793-799).
  • Particularly suitable for the process according to the invention are the phase transfer catalysts tris [2- (2-methoxy) ethoxy] ethylamine (TDA-1) or tris [2- (2-ethoxy) ethoxy] ethylamine (TDA-2), more preferably TDA-1 is used.
  • the invention relates to a method as described above, characterized in that the phase transfer catalyst is a tris (polyoxaalkyl) amine.
  • the process according to the invention is carried out in the presence of TDA-1.
  • the bases are sodium, NaH, NaNH 2 , Na or K alkoxide, NaOH or KOH.
  • Na or K alkoxides for example sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide. Particular preference is given to using potassium tert-butoxide in the process according to the invention.
  • the use of the base can be omitted partially or completely, if instead of the trifluoroethanol a corresponding trifluoroethanolate is used.
  • sodium or potassium trifluoroethanolate is suitable for the process according to the invention.
  • the invention relates to a method as described above, characterized in that the base from the group sodium, NaH, NaNH 2 , Na or K alkoxide, NaOH or KOH is selected.
  • copper salts are understood to mean copper (I) salts, for example Cu (I) acetate, Cu (I) Br, Cu (I) Cl, Cu (I) I, Cu (I) oxide, or Cu (I) rhodanide.
  • copper salts Cu (I) Cl, Cu (I) Br or Cu (I) I are suitable according to the invention, the use of Cu (I) Br being particularly preferred.
  • the invention likewise provides a process as described above, characterized in that copper (I) iodide or copper (I) bromide is used as the copper salt.
  • the reaction according to the invention is preferably carried out at temperatures between 10 and 80 ° C., more preferably at temperatures between 50 and 70 ° C. Most preferably, the reaction is carried out at the boiling point of the tetrahydrofuran.
  • the temperature control of the process according to the invention is chosen so that the reactants are first mixed at temperatures below 35 ° C, preferably between 10 ° and 30 ° C, more preferably at 20 ° C and the temperature thereafter to the actual reaction temperature between 50 ° and 80 °, in particular to the boiling point of tetrahydrofuran, is increased.
  • the invention also provides a method as described, characterized in that one carries out the reaction at temperatures between 10 ° and 80 ° C.
  • the invention relates to a method as described above, wherein the reactants are mixed at a temperature below 35 ° C and the temperature of the reaction mixture is raised to a reaction temperature between 50 ° and 80 ° C.
  • starting materials with regard to the description of the temperature control, all components of the reaction are summarized.
  • starting materials includes THF, the base, the phase transfer catalyst, trifluoroethanol, the copper salt and a halogenated benzoic acid of the formula II (in connection with the temperature control).
  • the invention also provides a process as described, characterized in that the reaction mixture is worked up acidic.
  • the acidic hydrolysis is preferably carried out with an acid selected from a group of acids to which organic acids, preferably formic acid, acetic acid or propionic acid, or also inorganic acids, preferably sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid or phosphoric acids such as orthophosphoric include.
  • Hydrochloric acid is particularly preferably used.
  • At least 1 mole of 2,2,2-trifluoroethanol per halogen atom of a compound of the formula II is used, preference being given to working with an excess of trifluoroethanol. Particular preference is given to using 3 mol of 2,2,2-trifluoroethanol per halogen atom of a compound of the formula II.
  • At least 1 mole of 2,2,2-trifluoroethanol per mole of base is used.
  • the molar ratio of copper salt to a compound of formula II may be 0.01: 1 to 2: 1. Particularly preferred is a molar ratio of 1: 1.
  • the molar ratio of phase transfer catalyst to a compound of formula II may be 0.01: 1 to 1: 1.
  • a molar ratio of 0.1: 1 to 0.5: 1 is preferred, and a molar ratio of 0.2: 1 is very particularly preferred.
  • the invention further provides a process for the preparation of trifluoroethoxy-substituted benzoic acid derivatives of the formula I, which comprises initially charging the base and / or the phase transfer catalyst in THF, optionally the phase transfer catalyst or the base, if they have not been added together , then adding 2,2,2-trifluoroethanol is added dropwise and this reaction mixture successively or simultaneously in any Order the copper salt and the corresponding halogenated benzoic acid of formula II inflicts. After a reaction time of a few minutes to several hours, the reaction mixture is cooled and the acid added as described above. The work-up of the reaction mixture is carried out by techniques known to those skilled in the art or as illustrated in the following examples.
  • the temperature is given in ° C.
  • the pH value corresponds to the decadic logarithm of the H + ion concentration.
  • the purity of the product is determined by HPLC.

Claims (3)

  1. Procédé pour la préparation d'acides benzoïques substitués par trifluoroéthoxy de la formule I
    Figure imgb0009
    dans laquelle
    R, R1 chacun indépendamment l'un de l'autre, représentent A, OA, COOH, COOA, SA, CF3, OCF3, CN, NO2, Hal, -(CH2)p-Hal, -O-(CH2)p-Hal, -S-(CH2)p-Hal, Ar, -(CH2)p-Ar, OAr, O(CO)Ar, NH2, NHA, NA2, CONH2, CONHA ou CONA2,
    A représente un radical alkyle comportant de 1 à 4 atomes de C,
    Ar représente phényle ou naphthyle, dont chacun est non substitué ou mono-, di- ou trisubstitué par A, OH, OA, CF3, OCF3, CN ou NO2,
    Hal représente F, CI, Br ou I,
    n représente 1, 2 ou 3,
    m, o chacun indépendamment l'un de l'autre, représentent 0, 1 ou 2,
    p représente 1 ou 2,
    par réaction d'un composé de la formule II
    Figure imgb0010
    dans laquelle
    X représente Cl, Br ou I et
    R, R1, A, Ar, Hal, n, m, o et p présentent la signification indiquée selon la formule I,

    où, pour n>1, X peut être identique ou différent,
    caractérisé en ce que
    du tert-butoxyde de potassium et un tris(polyoxaalkyl)amine en tant que catalyseur de transfert de phase sont présentés dans THF, le catalyseur de transfert de phase, lorsqu'il est utilisé, ou la base, s'ils n'ont pas été introduits ensemble, est ensuite ajoutée, du 2,2,2-trifluoroéthanol est ajouté au goutte-à-goutte, et du bromure de cuivre(I) et de l'acide benzoïque correspondant de la formule II sont ajoutés en succession ou simultanément à ce mélange de réaction selon n'importe quelle séquence souhaitée,
    et une élaboration acide est ensuite mise en oeuvre.
  2. Procédé selon la revendication 1, caractérisé en ce que la réaction est mise en oeuvre à des températures entre 10° et 80°C.
  3. Procédé selon la revendication 1 ou 2, caractérisé en ce que de l'acide 2,5-bis(2,2,2-trifluoroéthoxy)benzoïque est préparé.
EP01960238A 2000-05-26 2001-05-23 Procede de production d'acides benzoiques substitues par trifluoroethoxy Expired - Lifetime EP1309538B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10025700A DE10025700A1 (de) 2000-05-26 2000-05-26 Verfahren zur Herstellung von trifluorethoxysubstituierten Benzoesäuren
DE10025700 2000-05-26
PCT/EP2001/005923 WO2001090062A2 (fr) 2000-05-26 2001-05-23 Procede de production d'acides benzoiques substitues par trifluoroethoxy

Publications (2)

Publication Number Publication Date
EP1309538A2 EP1309538A2 (fr) 2003-05-14
EP1309538B1 true EP1309538B1 (fr) 2006-01-11

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EP01960238A Expired - Lifetime EP1309538B1 (fr) 2000-05-26 2001-05-23 Procede de production d'acides benzoiques substitues par trifluoroethoxy

Country Status (16)

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US (1) US6849762B2 (fr)
EP (1) EP1309538B1 (fr)
JP (1) JP2003534319A (fr)
KR (1) KR20030005394A (fr)
AT (1) ATE315549T1 (fr)
AU (1) AU2001281785A1 (fr)
BR (1) BR0110488A (fr)
CA (1) CA2409853A1 (fr)
CZ (1) CZ20023648A3 (fr)
DE (2) DE10025700A1 (fr)
MX (1) MXPA02011612A (fr)
NO (1) NO20025652D0 (fr)
PL (1) PL358691A1 (fr)
SK (1) SK15832002A3 (fr)
WO (1) WO2001090062A2 (fr)
ZA (1) ZA200210300B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1918280A1 (fr) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Procédé de préparation de 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide et de ses sels
EP2109598A1 (fr) * 2006-12-21 2009-10-21 E. I. Du Pont de Nemours and Company Procede pour la synthese d'ethers acides aromatiques
TW201127806A (en) * 2009-09-02 2011-08-16 Du Pont Process for the synthesis of fluorinated ethers of aromatic acids
TW201127809A (en) * 2009-09-02 2011-08-16 Du Pont Process for the synthesis of fluorinated ethers of aromatic acids
TW201127805A (en) * 2009-09-02 2011-08-16 Du Pont Process for the synthesis of fluorinated ethers of aromatic acids
JP7289539B2 (ja) * 2017-05-19 2023-06-12 エトナ－テック， リミテッド 官能化されたフッ素化モノマーを製造する方法、フッ素化モノマー、及びそれを製造するための組成物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4952574A (en) * 1988-09-26 1990-08-28 Riker Laboratories, Inc. Antiarrhythmic substituted N-(2-piperidylmethyl)benzamides
IL120715A (en) * 1997-04-21 2000-07-16 Finetech Ltd Process for the preparation of (2,2,2,-trifluoroethoxy)benzoic acids

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Publication number Publication date
JP2003534319A (ja) 2003-11-18
DE10025700A1 (de) 2001-11-29
CA2409853A1 (fr) 2002-11-22
KR20030005394A (ko) 2003-01-17
DE50108686D1 (de) 2006-04-06
ATE315549T1 (de) 2006-02-15
NO20025652L (no) 2002-11-25
MXPA02011612A (es) 2003-03-27
US6849762B2 (en) 2005-02-01
SK15832002A3 (sk) 2003-03-04
CZ20023648A3 (cs) 2003-02-12
NO20025652D0 (no) 2002-11-25
WO2001090062A3 (fr) 2003-03-06
EP1309538A2 (fr) 2003-05-14
ZA200210300B (en) 2004-09-06
US20030176721A1 (en) 2003-09-18
WO2001090062A2 (fr) 2001-11-29
PL358691A1 (en) 2004-08-09
BR0110488A (pt) 2003-04-01
AU2001281785A1 (en) 2001-12-03

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